A meta-analysis of randomized controlled trials comparing irinotecan/platinum with etoposide/platinum in patients with previously untreated extensive-stage small cell lung cancer

Jiang J, Liang X, Zhou X, Huang L, Huang R, Chu Z, Zhan Q

CRD summary

The review found that irinotecan with platinum may be associated with higher overall response and survival rates than etoposide with platinum for previously untreated extensive-stage small cell lung cancer, with a differing side-effect profile. The authors suggested that their findings required cautious interpretation: this appears justified in view of the heterogeneity, small number and questionable quality of the primary studies.

Authors' objectives

To compare the efficacy and safety of irinotecan with platinum versus etoposide with platinum for previously untreated extensive-stage small cell lung cancer.

Searching

PubMed and Cochrane Central Register of Controlled Trials (CENTRAL) were searched in April 2009. Search terms were reported. PDQ and ClinicalTrials.gov databases, annual meeting abstracts for the previous 10 years of the American Society of Clinical Oncology and European Society for Medical Oncology and reference lists of primary studies and reviews were searched. The search was unlimited by language or publication status.

Study selection

Randomised controlled trials (RCTs) that compared IP (irinotecan with cisplatin or carboplatin) with EP (etoposide with cisplatin or carboplatin) in individuals with previously untreated pathologically confirmed small cell lung cancer with clinically diagnosed extensive-stage disease were eligible for inclusion.

Participants in the included studies were predominantly male (range 55% to 90%). Median age ranged from 51 to 68 years. The proportion of participants with a good performance status (such as World Health Organisation 0-1) ranged from 52% to 100%. The dose-intensity of interventions differed across studies.

Outcomes reported in the review were overall response to treatment, overall and progression-free survival, grade three or four toxicity and treatment-related death. Study settings included Japan and North America.

The authors did not state how many reviewers performed study selection.

Assessment of study quality

Study quality was evaluated using the Jadad scale of adequacy of reported randomisation, double-blinding and withdrawals or dropouts.

Two reviewers independently assessed study validity. Disagreements were resolved by discussion with a third reviewer.

Data extraction

Relative risks for response rates, hazard ratios (HRs) for survival and odds ratios (ORs) for toxicity were extracted or calculated for each study, all with 95% confidence intervals (CIs). Where the hazard ratio was not reported, it was estimated from Kaplan-Meier curves using published methods (Parmar 1998). Intention-to-treat analysis was used for efficacy outcomes and treatment-received analysis for toxicity outcomes.

Two reviewers independently extracted data. Disagreements were resolved by discussion with a third reviewer.

Methods of synthesis

Studies were combined by meta-analysis to obtain pooled effect estimates and 95% CIs. Fixed-effect models were used unless there was significant heterogeneity, in which case random-effects models were used. Heterogeneity was assessed using Χ2. Publication bias was assessed using funnel plots and Begg’s and Egger’s tests. Subgroup analyses were conducted by type of platinum used (cisplatin or carboplatin).

Results of the review

Six RCTs were included in the review (n=1,476, range 30 to 327). Two RCTs (n=137) were Phase II (small preliminary studies). Quality scores were 2 (four RCTs), 3 (one RCT) and 4 (one RCT) from a possible maximum of 5. Only one RCT was double-blinded.

IP was associated with significantly higher rates of overall response to treatment (RR 1.10, 95% CI 1.00 to 1.21; five RCTs) and overall survival (HR 0.81, 95% CI 0.66 to 0.99; four RCTs) than EP. There was no significant difference between the groups in progression-free survival (four RCTs).

There was significant heterogeneity in the analyses of overall survival (I2=67%), progression-free survival (I2=79%) and neutropaenia (I2=84%). No evidence of significant publication bias was found. Subgroup analyses restricted to studies that used cisplatin found no significant difference between the groups for efficacy outcomes.

Authors' conclusions

IP may be associated with higher overall response and survival rates than EP in individuals with previously untreated extensive-stage small cell lung cancer, with a differing side-effect profile.

CRD commentary

The objectives and inclusion criteria of the review were clear. Relevant sources were searched for studies. There were no restrictions by language and publication status. Appropriate tests were used to assess for publication bias. Steps were taken to minimise risks of reviewer bias and error by having more than one reviewer undertake validity assessment and data extraction; it was unclear whether this also applied to study selection.

Overall study quality appeared to be poor, but no details were reported and study quality was hardly mentioned in the interpretation of results. Appropriate statistical techniques were used to combine the studies and assess for heterogeneity. There was significant heterogeneity for some outcomes, which the authors suggested might relate to differences in participant ethnicity and in the type and dose-intensity of the drugs used.

The authors suggested that their findings required cautious interpretation: this appears justified in view of the heterogeneity, small number and questionable quality of the primary studies.

Implications of the review for practice and research

Practice: The authors stated that IP may be an alternative to EP for first-line treatment of extensive-stage small cell lung cancer.

Research: The authors stated that the outcomes of ongoing studies were eagerly awaited and that an individual patient data meta-analysis was required.

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.